Biochemical and Molecular Characterization of a Small Molecule Modulator of Chromatin States

Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform based on the de novo enhancers and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility. Here, we report the identification of MS0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci. MS0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that MS0621 associates with EWSR1::FLI1, RNA binding and splicing proteins, as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWSR1::FLI1 and its known interactors, were RNA-independent. Additionally, we observed RNA-dependent interactions between MS0621 and members of both Polycomb Repressive Complexes (PRC1 and PRC2). Our findings suggest that MS0621 affects EWSR1::FLI1-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts.Doctor of Philosoph

La gestión de conflictos: Estilos de gestión e inteligencia emocional. Estudio de un caso

Estudio piloto de la relación entre los estilos de gestión de conflicto y la inteligencia emocional de una muestra

Fatores de risco para a saúde de escolares residentes em agrovilas

As crianças e jovens estão adotando condutas e hábitos, as quais podem prejudicar futuramente a sua vida, são os fatores de risco para a saúde como uso abusivo de álcool e outras drogas, inatividade física, envolvimento em brigas e falta do uso de equipamentos de segurança no transito. Com o objetivo de analisar estes comportamentos de risco para a saúde em estudantes residentes em agrovilas da região do município de Sousa-PB, foi utilizado uma pesquisa descritiva e transversal, por meio da aplicação do questionário Youth Risk Behavior Surveillance System (YRBSS). A amostra foi composta por 137 estudantes matriculados nas escolas estaduais das agrovilas, de ambos os sexos. Os dados foram tabulados e analisados pelo programa Epi info. Os principais resultados obtidos foram: cerca de 85% dos entrevistados estavam inativos fisicamente, porem 63,5% responder ter um deslocamento ativo para a escola, 55,88% participam de todas as aulas de educação física, tanto teórica quanto prática; já em relação a uso de cinto de segurança as meninas pareceram ser mais precavidas, cerca de 27,78% delas uso cinto de segurança sempre, já os meninos cerca de 15,38% não o usam nunca; com o uso de capacete cerca de 23,94% dos meninos responderam que nunca usam e 32,31% das meninas; 40% da população respondeu está satisfeito com seu peso corporal e 35,04% disseram nunca ter tomado iniciativa para mudar seu peso; já em relação a uso de álcool e outras drogas eles foram bem sucintos, responderam que nunca tinham experimentado cigarro (96,35%) e 67,15% nunca tomou bebida alcóolica; 100% dos entrevistados relataram nunca ter tido relações sexuais. Portando verifica-se que o âmbito escolar é de grande importância para o desenvolvimento de temas transversais trabalhados nas aulas de educação física, para a contribuição da formação do pensamento dos adolescentes

MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing

Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform based on the de novo enhancers and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility. Here, we report the identification of MS0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci. MS0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that MS0621 associates with EWSR1::FLI1, RNA binding and splicing proteins, as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWSR1::FLI1 and its known interactors, were RNA-independent. Our findings suggest that MS0621 affects EWSR1::FLI1-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts

Un examen actualizado de la percepción de las barreras para la implementación de la farmacogenómica y la utilidad de los pares fármaco/gen en América Latina y el Caribe

La farmacogenómica (PGx) se considera un campo emergente en los países en desarrollo. La investigación sobre PGx en la región de América Latina y el Caribe (ALC) sigue siendo escasa, con información limitada en algunas poblaciones. Por lo tanto, las extrapolaciones son complicadas, especialmente en poblaciones mixtas. En este trabajo, revisamos y analizamos el conocimiento farmacogenómico entre la comunidad científica y clínica de ALC y examinamos las barreras para la aplicación clínica. Realizamos una búsqueda de publicaciones y ensayos clínicos en este campo en todo el mundo y evaluamos la contribución de ALC. A continuación, realizamos una encuesta regional estructurada que evaluó una lista de 14 barreras potenciales para la aplicación clínica de biomarcadores en función de su importancia. Además, se analizó una lista emparejada de 54 genes/fármacos para determinar una asociación entre los biomarcadores y la respuesta a la medicina genómica. Esta encuesta se comparó con una encuesta anterior realizada en 2014 para evaluar el progreso en la región. Los resultados de la búsqueda indicaron que los países de América Latina y el Caribe han contribuido con el 3,44% del total de publicaciones y el 2,45% de los ensayos clínicos relacionados con PGx en todo el mundo hasta el momento. Un total de 106 profesionales de 17 países respondieron a la encuesta. Se identificaron seis grandes grupos de obstáculos. A pesar de los continuos esfuerzos de la región en la última década, la principal barrera para la implementación de PGx en ALC sigue siendo la misma, la "necesidad de directrices, procesos y protocolos para la aplicación clínica de la farmacogenética/farmacogenómica". Las cuestiones de coste-eficacia se consideran factores críticos en la región. Los puntos relacionados con la reticencia de los clínicos son actualmente menos relevantes. Según los resultados de la encuesta, los pares gen/fármaco mejor clasificados (96%-99%) y percibidos como importantes fueron CYP2D6/tamoxifeno, CYP3A5/tacrolimus, CYP2D6/opioides, DPYD/fluoropirimidinas, TMPT/tiopurinas, CYP2D6/antidepresivos tricíclicos, CYP2C19/antidepresivos tricíclicos, NUDT15/tiopurinas, CYP2B6/efavirenz y CYP2C19/clopidogrel. En conclusión, aunque la contribución global de los países de ALC sigue siendo baja en el campo del PGx, se ha observado una mejora relevante en la región. La percepción de la utilidad de las pruebas PGx en la comunidad biomédica ha cambiado drásticamente, aumentando la concienciación entre los médicos, lo que sugiere un futuro prometedor en las aplicaciones clínicas de PGx en ALC.Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC

Development, characterisation and in vitro evaluation of lanthanide-based FPR2/ALX-targeted imaging probes

UK Engineering and Physical Sciences Research Council (EPRSC); Royal Society Wolfson Fellowship

Biological Earth observation with animal sensors

Space-based tracking technology using low-cost miniature tags is now delivering data on fine-scale animal movement at near-global scale. Linked with remotely sensed environmental data, this offers a biological lens on habitat integrity and connectivity for conservation and human health; a global network of animal sentinels of environmen-tal change

Influence of climatic variables on the number of cases of visceral leishmaniasis in an endemic urban area

# Background Visceral leishmaniasis (VL) is a neglected tropical disease endemic in several countries, with as much as 97% of cases in the Americas attributable to Brazil. Despite considerable investment in disease control, Belo Horizonte is one of the Brazilian municipalities with the highest mortality rates. The present study aimed to investigate the association between climatic variables and the increase in the number of VL cases in Belo Horizonte. # Methods The study analyzed 1,897 laboratory-confirmed cases of VL registered by the municipality's Epidemiological Surveillance from 1994 to 2019. The climatic variables were obtained from the National Institute of Meteorology. # Results The first reported VL case was detected in 1994, and since then, the disease has spread throughout the municipality. The disease was most common in the very young age groups, 1 to 4 years, and older groups, 40 to 49 years old. Approximately 63% of detected cases were men. A peak number of cases were observed in 2004, 2006, 2008 and 2017. Total precipitation was significantly associated with the number of VL cases, with more cases depending on rainfall (P=0.006), thus confirming that climate contributes to the disease spread. # Conclusions These results demonstrate the need for the actions of the Visceral Leishmaniasis Surveillance and Control Program to be reinforced in years with above-average rainfall, a situation that is increasingly more frequent in Southeastern Brazil due to global climate change

Bloqueo Perirrectal En Cirugía Anorrectal

Proctological pathologies affect approximately 5% of the entire population and have a negative impact on the effective performance of basic life activities, which is why the prevention, diagnosis and prompt management are a fundamental part of medical care provided by care staff. Anorectal surgery has evolved over the years due to the need to implement fast, effective and specific techniques that guarantee the timely and total recovery of patients for early hospital discharge, therefore, today the type of anesthesia that is used is the main focus of attention. Local anesthesia such as perirectal nerve block alone or combined with intravenous sedation has been the chosen approach because it guarantees patient comfort by significantly reducing side effects, pain and prolonged hospital stays. In this paper you will find a systematic review of specific data on perirectal blockade in anorectal surgery as an effective alternative to general or regional anesthesia in order to expand the associated knowledge and promote the optimization of the results achieved.Las patologías de origen proctológico afectan aproximadamente al 5% de toda la población y repercuten de manera negativa en la realización efectiva de las actividades básicas de la vida diaria por lo que su prevención, diagnóstico y manejo oportuno son pilar fundamental de la atención médica brindada por el personal asistencial. La cirugía anorrectal ha evolucionado a través de los años debido a la necesidad de implementar técnicas rápidas, eficaces y específicas que permitan garantizar la recuperación oportuna y total de los pacientes para el egreso hospitalario temprano por lo que, en la actualidad, el tipo de anestesia a emplear es de igual manera foco de atención principal. La anestesia local como el bloqueo perirrectal solo o combinado con analgosedación intravenosa ha sido el abordaje preferido debido a que logra garantizar la comodidad del paciente reduciendo de manera significativa los efectos secundarios, el dolor y las estancias hospitalarias prolongadas. En este documento se encontrará una revisión sistemática de datos específicos sobre el bloqueo perirrectal en cirugía anorrectal como alternativa eficaz de la anestesia general o regional con el fin de ampliar el conocimiento asociado y promover la optimización de los resultados alcanzados

Image_4_MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing.jpeg

Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform based on the de novo enhancers and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility. Here, we report the identification of MS0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci. MS0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that MS0621 associates with EWSR1::FLI1, RNA binding and splicing proteins, as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWSR1::FLI1 and its known interactors, were RNA-independent. Our findings suggest that MS0621 affects EWSR1::FLI1-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts.</p